PONE-D-25-04818Factors Affecting Quality of Life in Connective Tissue Disease-Related Interstitial Lung DiseasePLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This is an interesting study that investigated the quality of life and its associated factors in patients with CTD-ILD. This is an important study but there are several things to be clarified.

1. The rationale that the authors selected SF-6D to assess quality of life in patients with CTD-ILD should be clarified. Although SF-6D is a good and representative tool to assess QOL, patients with CTD have lots of symptoms other than ILD.

2. Only 66.1% of the participants were treated with immunosuppressive medications. I wonder if those patients would be really representative of CTD-ILD. And before that, what was the definition of immunosuppressive medications? If that include glucocorticoids, synthetic immunosuppressive drugs, and also biological agents, the details should be described.

3. Demographics and disease characteristics of the participants should be tabulated in one table at first.

4. “The type of ILD” should be “the type of CTD” in Table 4.

5. The authors should explain and discuss more clearly what clinical impact this study would make.

Reviewer #2: Manuscript ID PONE-D-25-04818

"Factors Affecting Quality of Life in Connective Tissue Disease-Related Interstitial Lung Disease"

General comments

This cross-sectional study utilizing a secondary data analysis from the Pulmonary Fibrosis Foundation Patient Registry (PFFPR) investigated the association between patient demographic and disease characteristics, symptoms, and QOL in CTD-ILD. As the authors stated, the impact of CTD-ILD on QOL has yet to be sufficiently described due to the paucity of information about QOL in this population. Therefore, this study is important as the patient-centered outcomes research. Especially, examination for the mediation effects is interesting and important.

1. Quality of life (QOL) and health-related quality of life (HRQoL)

Quality of life (QOL) is a broad term defined as an individual’s wellbeing in relation to their goals and expectations, in the context of the cultural and value systems they live in (WHO). Health-related quality of life (HRQoL) is a subset of QOL that describes an individual’s perception of the impact of health, disease, and treatment on their QOL.

The authors used Medical Outcome Study Short Form Six-Dimension Health Survey (SF-6D) as one of the patient reported outcome measures (PROMs) in this study. SF-6D, as well as the Medical Outcome Study 36-Item Short Form Health Survey (SF-36), is a generic measure for HRQoL. Most papers the authors cited in this manuscript are related to HRQoL rather than QOL. Considering that HRQoL refers to the impact of physical and mental health on an individual’s QOL, the authors should be caution in use of the term ‘QOL’. I recommend to use the term ‘HRQoL’ instead of ‘QOL’ in many parts in this manuscript.

2. Significance of supplemental oxygen use and pulmonary rehabilitation

According to the results of this study the authors mentioned that supplemental oxygen use was associated with poorer QOL and there was a statistically significant difference in QOL with those participating in pulmonary rehabilitation reporting poorer QOL.

I am worried about the negative impact of supplemental oxygen use and pulmonary rehabilitation in clinical practice for patients with CTD-ILD. I recommend to add some comments on these points in the DISCUSSION section as I pointed out in the Minor comments.

3. Study population regarding race

The authors stated that 78% of the individuals were White and 18% were Black, traditionally not seen in the CTD-ILD population. As the authors mentioned in the DISCUSSION section, in the United States, Black individuals often have less access to specialized healthcare, which may have influenced the study’s inclusion process and potentially led to selection bias. How about the percentage of White and Black in the original PFFPR population? Are there any differences in the percentage of White and Black between the original PFFPR population and the CTD-ILD population in this study?

Minor comments

INTRODUCTION

P3

・The mortality rate for ILD has increased over 50% in the past 10 years and is the 40th most common cause of death.2

The authors should add the information about countries and territories in this study.2 This study, the Global Burden of Disease 2015 Study (GBD 2015), provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015.

・Connective tissue disease (CTD) is responsible for approximately one third of all cases.4

The paper you cited as #4 (Cochrane Database Syst Rev. 2018;1(1): CD010908) is the Cochrane Review for cyclophosphamide therapy for CTD-ILD. The correct paper you should cite here is ‘Mittoo S, Gelber AC, Christopher-Stine L, Horton MR, Lechtzin N, Danoff SK. Ascertainment of collagen vascular disease in patients presenting with interstitial lung disease. Respiratory Medicine 2009;103:1152-8.’

The paper #4 describes as follows; ‘Approximately 30% of individuals with ILD have associated CTD, which presents subsequent to the development of ILD in about 15% of these individuals (Mittoo S, Gelber AC, Christopher-Stine L, Horton MR, Lechtzin N, Danoff SK. Ascertainment of collagen vascular disease in patients presenting with interstitial lung disease. Respiratory Medicine 2009;103:1152-8.).

RESULTS

Descriptive Analyses

P7

・Most participants did not require supplemental oxygen (206 [61.9%]), were not taking immunosuppressant medications (220 [66.1%]),・・・

Could the authors describe the type of immunosuppressant medications; glucocorticoids, other disease-modifying anti-rheumatic drugs (DMARDs) or other immunomodulatory agents, in the study population? Although the authors mentioned that QOL was not associated with immunosuppressive medication use, in patients with rheumatoid arthritis the impact of glucocorticoids on HRQoL has been investigated from the perspective of the patient (Cheah JTL, et al. The patient's perspective of the adverse effects of glucocorticoid use: A systematic review of quantitative and qualitative studies. From an OMERACT working group. Semin Arthritis Rheum. 2020;50(5):996-1005.). Our readers may want to know the type of immunosuppressant medications.

DISCUSSION

P16

・A recent study found that Whites were more than twice as likely than Blacks to receive care at an academic medical center.27

These findings could be changed by different countries or territories. The authors should add the information about territories studied in this study, that is, Boston and New York City.27

・Supplemental oxygen use was associated with poorer QOL as hypothesized.

I recommend to add some comments on the effects of supplemental oxygen on HRQoL in ILD patients using the following paper showing that ambulatory oxygen seems to be associated with improved HRQoL in patients with ILD.

Visca D, et al. Effect of ambulatory oxygen on quality of life for patients with fibrotic lung disease (AmbOx): a prospective, open-label, mixed-method, crossover randomised controlled trial. Lancet Respir Med. 2018;6(10): 759-770.

P17

・It was hypothesized that the use of immunosuppressant medication was associated with poorer QOL, based on similar findings in the renal transplant community citing side effects of immunosuppressant drugs.35,36

The authors described the different situations for immunosuppressant medication use between CTD-ILD patients and renal transplant patients.

As mentioned above, in patients with rheumatoid arthritis the impact of glucocorticoids on HRQoL has been investigated (Cheah JTL, et al. The patient's perspective of the adverse effects of glucocorticoid use: A systematic review of quantitative and qualitative studies. From an OMERACT working group. Semin Arthritis Rheum. 2020;50(5):996-1005.). In addition, in patients with sarcoidosis, glucocorticoids can reportedly negatively affect HRQoL (Judson MA, et al. The effect of corticosteroids on quality of life in a sarcoidosis clinic: the results of a propensity analysis. Respir Med. 2015;109(4):526-31. Cox CE, et al. Health-related quality of life of persons with sarcoidosis. Chest 2004;125(3):997-1004.). Do you have any additional comments on the effects of immunosuppressant medication, especially for glucocorticoids, for HRQoL in CTD-ILD patients? CTD-ILD and sarcoidosis may have similar situations for immunosuppressant medication use.

P18

・Perhaps there may have been improvement in their QOL after completion of a pulmonary rehabilitation program.

I recommend to add some comments about the effects of pulmonary rehabilitation for ILD on HRQoL using a paper showing that pulmonary rehabilitation probably improves HRQoL (Dowman L, Hill CJ, May A, Holland AE. Pulmonary rehabilitation for interstitial lung disease. Cochrane Database Syst Rev. 2021; 2(2): CD006322.). In addition, recently published systematic review for pulmonary rehabilitation in CTD-ILD shows that pulmonary rehabilitation benefits moderate levels of evidence for quality of life in CTD-ILD patients (Seleoglu I, Demirel A. Pulmonary rehabilitation in connective tissue disease-associated interstitial lung disease: A systematic review. Sarcoidosis Vasc Diffuse Lung Dis. 2024; 41(4): e2024061).

・Mediation Effects

The authors reported that the symptom of cough did not mediate any of the relationships between the antecedents and QOL in the RESULTS section.

I recommend to add some comments on these results because this may signify the importance of cough as one of the PROMs. Worse cough severity is reportedly independently associated with worse HRQoL in fibrotic ILD (Khor YH, et al; CARE-PF Investigators. Epidemiology and prognostic significance of cough in fibrotic interstitial lung disease. Am J Respir Crit Care Med. 2024; 210(8): 1035-1044.)

Reviewer #3: This is a very valuable paper that considers the quality of life of patients with CTD-ILD. There are no particular problems with the theme or the main content, and I think it is an important study in today's world where patient-centred medicine is talked about.

<minor comments="">

In this study, FVC and supplemental oxygen are being examined, but I wonder if DLco is not being examined?

Also, can you mention whether or not Shortness of breath in Symptom A occurs during exertion, such as during a six-minute walk test? If there is CTD, there is a possibility that there are latent vascular lesions, for example in scleroderma, and SOB during exertion may have a stronger impact on QOL.

P2L16: paticipants → participants

P2L25: pallpiative → palliative</minor>

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Reviewer #1: No

Reviewer #2: Yes:  Hiromi Tomioka

Reviewer #3: No

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Factors Affecting Quality of Life in Connective Tissue Disease-Related Interstitial Lung Disease

PONE-D-25-04818R1

Dear Dr. Ohare,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Masataka Kuwana, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: General comments

The authors replied appropriately and revised the manuscript.

Minor comments

KEY WORDS:

quality of life→health-related quality of life

Table 1. Variable

Quality of life→Health-related quality of life

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Reviewer #1: No

Reviewer #2: Yes:  Hiromi Tomioka

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